The research project is directed toward three separate but interrelated goals: 1) The evaluation of the acute toxic liability of candidate biomaterials using Primary Acute Toxicity Screening protocols for the assessment of in vitro and in vivo response. Validation of the predictive relationships among the tests and validation with respect to higher order histopathological response to implanted biomaterials are primary objectives of the work. 2) The development of standard reference materials and/or known standard toxicant solutions for interlaboratory standardization of test protocols for acute toxicity testing of biomaterials. Materials standards are under development for tests directly on biomaterials and solution standards are under development for tests on extracts (leachables) of biomaterials. 3) An Osmotic Fragility test is under evaluation as a sensitive means for the detection and quantitation of primary cell membrane interactions of leachable substances of biomaterials. Relative fragility and cell size distribution with respect to concentration provide sensitive indicators of primary membrane interactions. The relationship of those parameters to acute toxic response to leachable components of biomaterials is a primary objective.